tbuckley/cabot-search huggingface dataset:
Abstract LB293: The evolution of MRD assays: Moving beyond the tumor-Informed bespoke NGS panel
Authors: Paul Labrousse, Daniel Stetson, James Hadfield, Chris Abbosh, Ahmet Zehir, Carl Barrett, Brian Dougherty, Darren Hodgson
Journal: Cancer Research (2023)

Abstract The non-invasive detection of circulating tumor DNA (ctDNA) from plasma has been shown to have clinical value for detection of minimal residual disease (MRD), identification of emerging resistance to treatment, and predicting treatment response. The ability to detect MRD following curative treatment allows for the stratification of patients with higher risk of disease recurrence. Multiple studies, across hundreds of patients in different indications, including lung and colon cancer, have shown that tumor-informed personalized assays have high sensitivity to detect recurrence. The tumor-informed bespoke panels utilize sequencing of the tumor tissue to identify clonal somatic variants, which are then used to generate a personalized panel to track the variants in patient plasma. Next-generation MRD technologies are aiming to provide greater sensitivity by expanding methods beyond the small, personalized panels. Utilization of increased numbers of somatic variants is predicted to achieve a greater level of sensitivity for detection of MRD. Here we describe, C2I Genomics which provides a novel platform that exploits whole genome sequencing of the tumor tissue and plasma to define a somatic variant signature. An important difference of this method is that it develops a personalized bioinformatic signature rather than a personalized NGS panel. To understand the potential of this novel methodology, we utilized a set of 54 contrived clinical sample dilutions from three indications, with an expected (or engineered) VAF range of 0.2-0.002%, that have commutability to the intended use population. We found that C2I Genomics technology is highly sensitive, where for all returned samples, the assay routinely achieved detection down to the lowest dilution of 0.002% allelic frequency. Overall, the assay resulted in an average detection rate of 93% across all dilutions (n = 54). The aggregate detection rate of several tumor-informed assays, examining the same dilutions, yielded a detection rate of 68%. In summary, the C2I Genomics assay showed robust detection from contrived samples which are representative of clinical trial samples in both cfDNA yields and allele frequency. Citation Format: Paul Labrousse, Daniel Stetson, James Hadfield, Chris Abbosh, Ahmet Zehir, Carl Barrett, Brian Dougherty, Darren Hodgson. The evolution of MRD assays: Moving beyond the tumor-Informed bespoke NGS panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB293.
Abstract LB230: Critical role for DAXX in triple negative breast cancer
Authors: Clodia Osipo, Debra Wyatt
Journal: Cancer Research (2023)

Abstract Breast cancer is the most common diagnosed cancer and second cause of mortality in women. In particular, triple negative breast cancer, a subtype with few targeted therapies, frequently presents with metastatic disease and drug resistance. Nearly half of women with triple negative breast cancer will have metastatic disease. New targets and therapies are needed to prevent drug resistance and metastatic disease. We identified a novel protein, DAXX, in a biomarker window trial as a potent inhibitor of breast cancer stem cells (BCSC). BCSC are responsible for drug resistance, metastases, and tumor relapse. In this current study, the role of DAXX in sensitivity to cytotoxic chemotherapy was investigated in the setting of triple negative breast cancer. DAXX depletion using RNAi increased the proliferative capacity of three triple negative breast cancer cell lines (MDA-MB-231, BT549, and MDA-MB-468). This corresponded with increased PARylation of cellular proteins and PARP-1. DAXX was required to limit cell cycle progression through S-phase. Knockdown of DAXX modulated sensitivity to carboplatin, doxorubicin, and paclitaxel in vitro. Survival of female nude mice-bearing MDA-MB-231 DAXX-depleted tumors was 100% upon paclitaxel treatment compared to vehicle control-treated mice where the survival rate was 0% after 30 days. This survival advantage was not due to differences in tumor burden or tumor growth rates. These results suggest that DAXX is a critical growth regulator of triple negative breast cancer and possible predictor of response to paclitaxel. Citation Format: Clodia Osipo, Debra Wyatt. Critical role for DAXX in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB230.
Abstract LB228: Replication stress activates the DNA damage response and contributes to lapatinib resistance in HER2-positive SK-BR-3 cells
Authors: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Yu Jin Kim, Sujin Ham, Hae Min Hwang, Minyoung Lee, Changyun Lee, Jinyong Kim, Dae-Won Lee, Kyung-Hun Lee, Seock-Ah Im
Journal: Cancer Research (2023)

Abstract Background: Lapatinib is a small molecular inhibitor of HER2 and EGFR tyrosine kinases, which is approved for HER2-positive metastatic breast cancer as second line treatment. Significant proportion of patients experience disease progression due to acquired resistance. Activation of DNA damage repair (DDR) is one of the drug-resistance mechanism, however, the impact of DDR on sensitivity to lapatinib is unclear. Thus, lapatinib resistance mechanism was explored from the standpoint of DDR activation. Methods: Acquired lapatinib-resistant (LR) SK-BR-3 cell lines were generated by continuously exposing to lapatinib, starting with 30 nmol/L and incrementally increasing to 10 μmol/L over 7 months. MTT assay was used to confirm lapatinib sensitivity. Cell cycle progression was analyzed using BrdU assay. Replication fork speed and stalled fork were analyzed by DNA fiber assay. Expression of the molecules was examined using Western blotting, immunofluorescence assay and transcriptome data analysis. DNA strand breaks and repair efficacy were evaluated through alkaline comet assay. Results: G1/S phase transition was increased and early/late S phase population was increased in SK-BR-3 LR cells. Replication fork speed was accelerated and replication stress are elevated in SK-BR-3 LR cells. p-Chk1, Rad51, Rad51B, Rad51C and XRCC3 were upregulated in SK-BR-3 LR cells. After irradiation or treatment with ATR inhibitor, γ-H2AX was continuously increased in parental cells. In contrast, γ-H2AX did not change significantly in SK-BR-3 LR cells, and Chk1 was activated after irradiation or treatment with ATR inhibitor. Tail of comet disappeared at early time point in in SK-BR-3 LR cells after induction of DNA damage compared with parental cells. These results demonstrated that DDR was activated and DNA damage repair capacity was enhanced in LR cells. Conclusion: Replication stress is elevated in SK-BR-3 LR cells. Up-regulation of molecules involved in the homologous recombination repair pathway was observed in SK-BR-3 LR cells. Moreover, DNA repair capacity was increased in SK-BR-3 LR cells. These data suggested that activation of DNA damage repair pathway caused by replication stress contributes to lapatinib resistance. Citation Format: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Yu Jin Kim, Sujin Ham, Hae Min Hwang, Minyoung Lee, Changyun Lee, Jinyong Kim, Dae-Won Lee, Kyung-Hun Lee, Seock-Ah Im. Replication stress activates the DNA damage response and contributes to lapatinib resistance in HER2-positive SK-BR-3 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB228.
Abstract LB292: GCC2 on small extracellular vesicles for the early diagnosis of lung adenocarcinoma: A multicenter trial
Authors: Byeong Hyeon Choi, Hyonggin An, Sukki Cho, Sungsoo Lee, Hyeong Ryul Kim, Jong Ho Cho, Hyunku Shin, Ok Hwa Jeon, Yeonho Choi, Hyun Koo Kim
Journal: Cancer Research (2023)

Abstract Background: Early detection of lung cancer is extremely important for timely and effective therapeutic interventions to increase the survival rate of patients. Emerging evidence suggests that tumor-derived small extracellular vesicle (sEV) cargo may serve as cancer-specific biomarkers. We previously reported the identification of GRIP and coiled-coil domain-containing 2-enriched sEV (sEV-GCC2) as a promising biomarker for lung adenocarcinoma in a pilot study. In this multicenter study, we explored the diagnostic and therapeutic potential of sEV-GCC2 in early-stage lung adenocarcinoma. Methods: A total of 470 blood plasma samples (150 healthy controls and 320 patients with lung adenocarcinoma) were retrospectively obtained from five institutions. sEVs were isolated by size exclusion chromatography and sEV-GCC2 was quantified by enzyme-linked immunosorbent assay. Effect of sEV-GCC2 on lung cancer cell proliferation was investigated in vitro and in vivo. Results: sEV-GCC2 concentration was significantly higher in patients than that in controls with an area under the curve (AUC) of 0.856 (95% confidence interval [CI], 0.820-0.886). In patients at TisN0-T1miN0 stages vs controls, the AUC was 0.802 (95% CI, 0.734-0.859). The association between sEV-GCC2 and lung adenocarcinoma remained after adjustment for pathological TNM stage and tumor location in the left lower lobe. Immunohistochemical staining revealed that GCC2 expression was significantly higher in lung adenocarcinoma tissues than in the controls (p &amp;lt; 0.001). Furthermore, sEV-GCC2 enhanced cancer cell proliferation and accelerated tumor growth and lymph node metastasis. Conclusions: We identified sEV-GCC2 as a potential diagnostic marker for very early-stage lung cancer. sEV-GCC2 represents a promising therapeutic target for lung adenocarcinoma and may be quantified as key molecules in the progression of lung adenocarcinoma. Citation Format: Byeong Hyeon Choi, Hyonggin An, Sukki Cho, Sungsoo Lee, Hyeong Ryul Kim, Jong Ho Cho, Hyunku Shin, Ok Hwa Jeon, Yeonho Choi, Hyun Koo Kim. GCC2 on small extracellular vesicles for the early diagnosis of lung adenocarcinoma: A multicenter trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB292.
Abstract LB322: Antitumor activity of 1st-in-class pan-RAS inhibitor ADT-1004 in mouse models of pancreatic ductal adenocarcinoma
Authors: Yulia Y. Maxuitenko, Jeremy B. Foote, Adam B. Keeton, Xi Chen, Kristy Berry, Khalda Fadlalla, Jacob Valiyaveettil, Chung-Hui Huang, Austin M. Moore, Emily C. Graff, Ganji P. Nagaraju, Julienne L. Carstens, Bassel F. El-Rayes, Donald J. Buchsbaum, Gary A. Piazza
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer death in the U.S. with only about a 10% five-year survival rate and an estimated 60,000 deaths/year by 2030. Poor survival is frequently due to advanced disease at the time of diagnosis, as well as the high prevalence of KRAS driver mutations. Currently, approved KRAS-targeted therapeutics are designed to covalently inactivate only KRAS-G12C mutants, whereas the most common mutations in PDA are KRAS-G12D, KRAS-G12V, and KRAS-G12R. Thus, the need for novel RAS-targeted therapeutics with efficacy in tumors with these more common mutations is of utmost urgency to reduce PDA disease burden. We have synthesized a novel chemical class of pan-RAS inhibitors with unique biological properties and attractive drug-like properties. As a prodrug, ADT-1004, generates an active metabolite, ADT-007, that potently inhibits the growth of human and murine PDA cell lines in vitro with single-digit nM IC50 irrespective of specific RAS mutational codon or isozyme by inhibiting activated RAS and signaling downstream of KRAS (ERK1/2 and AKT phosphorylation). ADT-1004 is well tolerated with no discernable toxicity at oral dosages of up to 175 mg/kg bid. Pharmacokinetic studies demonstrated that ADT-1004 produces sustained plasma concentrations of ADT-007 ~50-fold above IC50 values, with even higher concentrations in both subcutaneous and orthotopic pancreatic tumors. Once daily oral administration of ADT-1004 significantly inhibited the growth of orthotopically implanted PDA tumors with a corresponding reduction in RAS/MAPK signaling. ADT-1004 represents a 1st-in-class pan-RAS inhibitor with potential advantages over mutant-specific KRAS inhibitors for greater efficacy and ability to avert mechanisms of resistance. These data support future clinical trials of ADT-1004 as a monotherapy for the treatment of patients with PDA regardless of the underlying mutation. Citation Format: Yulia Y. Maxuitenko, Jeremy B. Foote, Adam B. Keeton, Xi Chen, Kristy Berry, Khalda Fadlalla, Jacob Valiyaveettil, Chung-Hui Huang, Austin M. Moore, Emily C. Graff, Ganji P. Nagaraju, Julienne L. Carstens, Bassel F. El-Rayes, Donald J. Buchsbaum, Gary A. Piazza. Antitumor activity of 1st-in-class pan-RAS inhibitor ADT-1004 in mouse models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB322.
Abstract LB104: Preclinical evaluation of the role of Galectin-1 in tumor immune evasion associated mechanisms using a highly selective Galectin-1 small molecule inhibitor
Authors: Ian Holyer, Rob Slack, Kristoffer Petersen, Fredrik Zetterberg, Alison Mackinnon
Journal: Cancer Research (2023)

Abstract Galectin-1 (Gal-1) is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment (TME) of some aggressive cancers and whose high expression correlates strongly with poor survival. Following a data mining exercise of external publication data and additional clinical biomarker datasets, we found strong evidence concluding the potential role of Gal-1 in the establishment of a fibrotic tumor stroma and mechanisms associated with tumor invasion, metastasis and angiogenesis. However, there was limited data regarding the role of Gal-1 in immune escape by tumors to make any strong conclusions/pathway reconstruction around this specific TME mechanism of action (MOA). To further strengthen the potential role of Gal-1 in tumor immune evasion we completed a series of preclinical in vivo and in vitro activities, using a highly selective Gal-1 small molecule inhibitor developed at Galecto Biotech. To examine the role of Gal-1 inhibition in vivo, we investigated the effects on tumor volume of the highly selective Gal-1 inhibitor, in a syngeneic mouse model of lung adenocarcinoma. RNA profiling of vehicle and compound treated tumors was also implemented following completion of the in-life phase. Oral administration of the Gal-1 inhibitor reduced mouse lung adenocarcinoma growth and increased the immune gene expression within the tumors, showing a strong association to that of exacerbated NK cell activity. No additional cytotoxic T cell gene changes were uncovered in the Gal-1 inhibitor treated tumors. We further evaluated the overall T cell compartment, relevant to the clinical TME setting, by stimulating human peripheral blood mononuclear cells (hPBMC’s) incubated with and without the Gal-1 inhibitor to observe the potential blockade of any known immune checkpoint inhibitor (ICI) resistance mechanisms. Interestingly, we found a variety of immune suppressive proteins to be inhibited, including IL-17, when hPBMC’s were incubated with the Gal-1 inhibitor. In summary, the data presented suggests highly selective Gal-1 inhibition could provide an effective, monotherapy (or be used in combination with ICI's) to boost immune infiltration and/or activation in the TME of lung adenocarcinoma and potentially other aggressive cancers. Citation Format: Ian Holyer, Rob Slack, Kristoffer Petersen, Fredrik Zetterberg, Alison Mackinnon. Preclinical evaluation of the role of Galectin-1 in tumor immune evasion associated mechanisms using a highly selective Galectin-1 small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB104.
Abstract LB132: <i>In silico</i> mutant neoantigen prediction - a promising avenue for target identification in human adrenocortical carcinoma
Authors: Laura-Sophie Landwehr, Silke Appenzeller, Laura Ölsner, Isabel Weigand, Silviu Sbiera, Martin Fassnacht, Matthias Kroiss
Journal: Cancer Research (2023)

Abstract Introduction: Adrenocortical carcinoma (ACC) is one of the most aggressive endocrine malignancies and confers a poor prognosis in advanced stages. Effective treatments are lacking. The results of immune checkpoint inhibition were disappointing with few responders only deriving clinical benefit. For the development of novel immunotherapies such as tumor vaccines and T cell-based treatments, target identification is essential. Tumor-specific mutant neoantigens that may be recognized by T cells in the context of major histocompatibility complex (MHC) I are promising candidates. Methods: We performed whole exome-sequencing in 10 ACC samples with matched blood controls. Somatic mutations were identified using an in house bioinformatics pipeline. By coupling POLYSOLVER for HLA typing with netMHCpan, in silico binding affinity of tumor-specific neoantigens to MHC was calculated taking into account both peptide and HLA sequence information. Strong binding (SB) was defined as &amp;lt;0.5% rank, weak binding (WB) as 0.5-1.9% rank and no binding (NB) as &amp;gt;2.0% rank of all peptides to MHC. Results: Across 10 ACC patients, we identified 1067 unique somatic mutations (median 49.5, ranging from 15-590), affecting 989 different genes. Binding affinity changed for 414 predicted neoantigens from NB to WB, 80 from NB to SB and 82 from WB to SB. The mutant neoantigen load per patient ranged from 10 to 235 (mean 66.2) and was positively correlated to the total number of non-synonymous single nucleotide variants (R2 0.8977, 95% CI 0.79-0.99; p&amp;lt;0.0001). Discussion: This is the first study that demonstrates successful in silico neoantigen profiling in ACC. Mutant neoantigens were predicted to be present both in ACC with high and low tumor mutational burden. These data will pave the way for in vitro validation and hold potential to develop therapeutic cancer vaccines and T cell-based cancer immunotherapy in ACC. Citation Format: Laura-Sophie Landwehr, Silke Appenzeller, Laura Ölsner, Isabel Weigand, Silviu Sbiera, Martin Fassnacht, Matthias Kroiss. In silico mutant neoantigen prediction - a promising avenue for target identification in human adrenocortical carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB132.
Abstract LB133: An orally bioavailable degrader targeting androgen receptor and the splice variant in castration resistant prostate cancer
Authors: Chiu-Lien Hung, Ling-Yu Wang, Chih-Wei Fu, Hung-Chih Hsu, Hsin-Jien Kung
Journal: Cancer Research (2023)

Abstract The development and progression of prostate cancer depends on androgen receptor (AR) whose sustained activity albeit the use of anti-androgen drugs accounts for one of the major mechanisms leading to drug resistance. As such, the clinical benefits of current therapeutic agents remain rather limited for the advanced prostate cancer. Given that expression of constitutively active AR variants (AR-Vs) that lack the ligand-binding domain (LBD) clinically associates with the drug resistance and poor survival, targeting both AR and the LBD-truncated AR-Vs is anticipated an effective approach to overcome therapy resistance. Here, we present Proteolysis Targeting Chimeras (PROTAC) compound ITRI-148, capable of effectively degrading both full-length and LBD-truncated AR by targeting the proteins via the N-terminal domain to Cereblon-mediated ubiquitination and degradation. Degradation of AR and AR-V7 suppresses target gene expression, and inhibits cell proliferation with accompanied apoptosis activation in AR-V7-expressing castration-resistant prostate cancer (CRPC) cell models. In vivo, this compound displays good pharmacokinetics profiles and oral bioavailability with strong antitumor efficacy towards castration-, enzalutamide-resistant CWR22Rv1 and VCaP xenograft models. These data provide compelling evidence that by targeting AR NTD for induced degradation of active AR protein variants, ITRI-148 is a promising agent for the intervention of advanced therapy-resistant prostate cancers. Citation Format: Chiu-Lien Hung, Ling-Yu Wang, Chih-Wei Fu, Hung-Chih Hsu, Hsin-Jien Kung. An orally bioavailable degrader targeting androgen receptor and the splice variant in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB133.